RAGE deficiency alleviates aortic valve calcification in ApoE-/- mice via the inhibition of endoplasmic reticulum stress
RAGE deficiency alleviates aortic valve calcification in ApoE-/- mice via the inhibition of endoplasmic reticulum stress
复制标题
RAGE缺陷通过抑制内质网应激减轻ApoE（-/-）小鼠的主动脉瓣钙化
DOI：
10.1016/j.bbadis.2016.12.012
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发表时间：
2017-03-01
影响因子：
6.2
通讯作者：
Li, Fei
中科院分区：
文献类型：
--
作者：
Wang, Bo;Cai, Zhejun;Li, Fei
晚期糖基化终末产物受体（Receptor for advanced glycation end products，ERK）和内质网应激（endoplasmic reticulum，ER）参与钙化性主动脉瓣疾病（calcificaortic valve disease，CAVD）的发生。然而，在CAVD的发病机制中，ER应激和ER之间的联系仍然未知。目前的研究旨在验证这一假设，即维生素D缺乏通过抑制ER应激而加重主动脉瓣钙化。免疫印迹证实钙化的人主动脉瓣中ER和ER应激标志物的上调。在动脉粥样硬化倾向的ApoE（-/-）小鼠或喂食高胆固醇饮食24周的ApoE和ApoE双缺陷（ApoE（-/-）ApoE（-/-））小鼠中评价主动脉瓣钙化。超声心动图和组织学检查显示，ApoE（-/-）小鼠的主动脉瓣钙化减弱了ApoE基因缺陷。同时，骨钙素缺乏抑制成骨信号和ER应激激活，并抑制体内巨噬细胞浸润。以培养的人主动脉瓣间质细胞（AVICs）为模型，用高分子组蛋白B1（HMGB 1）处理AVICs。我们发现，HMGB 1诱导成骨细胞分化和钙化，通过骨钙素/ ER应力。此外，Sox 9上调和核内易位介导了HMGB 1对AVIC的促成骨作用。HMGB 1可抑制单核细胞趋化蛋白-1（MCP-1）和肿瘤坏死因子-α（TNF-α）的表达，提示HMGB 1可抑制ApoE（-/-）小鼠主动脉瓣的钙化。HMGB 1通过ERK/ER应激/Sox 9途径诱导AVIC成骨细胞分化和钙化。(C)2016由Elsevier B. V.出版
Receptor for advanced glycation end products (RAGE) and endoplasmic reticulum (ER) stress have been shown to be involved in calcific aortic valve disease (CAVD). However, the association between RAGE and ER stress remains unknown in the pathogenesis of CAVD. The current study aims to test the hypothesis that RAGE deficiency alleviates aortic valve calcification via the inhibition of ER stress. Up-regulation of RAGE and ER stress markers in calcified human aortic valves were confirmed by immunoblotting. Aortic valve calcification was evaluated in atherosclerotic prone ApoE(-/-) mice or in mice with dual deficiencies of ApoE and RAGE (ApoE(-/-) RAGE(-/-)) fed with high cholesterol diet for 24 weeks. Echocardiography and histological examination show that genetic deficiency of RAGE attenuates aortic valve calcification in ApoE(-/-) mice. Meanwhile, RAGE deficiency inhibited the osteogenic signaling and ER stress activation as well as suppressed macrophage infiltration in vivo. Cultured human aortic valve interstitial cells (AVICs) were treated with high molecular group box 1 protein (HMGB1) as in vitro model. We found that HMGB1 induced osteoblastic differentiation and calcification through RAGE/ ER stress. Furthermore, Sox9 up-regulation and intranuclear translocation mediated the pro-osteogenic effect of HMGB1 on AVICs. RAGE or ER stress knockdown reduced the up-regulation of monocyte chemoattractant protein -1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) in human AVICs exposed to HMGB1.These novel findings demonstrate that RAGE deficiency protects against aortic valve calcification in high cholesterol diet-fed ApoE(-/-) mice via inhibition of ER stress. HMGB1 induces AVIC osteoblastic differentiation and calcification through RAGE/ER stress/Sox9 pathway. (C) 2016 Published by Elsevier B.V.